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Originally published In Press as doi:10.1074/jbc.M208247200 on November 21, 2002

J. Biol. Chem., Vol. 278, Issue 6, 3671-3678, February 7, 2003
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Human Autophagins, a Family of Cysteine Proteinases Potentially Implicated in Cell Degradation by Autophagy*

Guillermo MariñoDagger §, José A. UríaDagger , Xose S. PuenteDagger , Víctor QuesadaDagger §, Javier Bordallo||, and Carlos López-OtínDagger **

From the Dagger  Departamento de Bioquímica y Biología Molecular and || Area de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain

We have cloned four human cDNAs encoding putative cysteine proteinases that have been tentatively called autophagins. These proteins are similar to Apg4/Aut2, a yeast enzyme involved in the activation of Apg8/Aut7 during the process of autophagy. The identified proteins ranging in length from 393 to 474 amino acids also contain several structural features characteristic of cysteine proteinases including a conserved cysteine residue that is essential for the catalytic properties of these enzymes. Northern blot analysis demonstrated that autophagins are broadly distributed in human tissues, being especially abundant in skeletal muscle. Functional and morphological analysis in autophagy-defective yeast strains lacking Apg4/Aut2 revealed that human autophagins-1 and -3 were able to complement the deficiency in the yeast protease, restoring the phenotypic and biochemical characteristics of autophagic cells. Enzymatic studies performed with autophagin-3, the most widely expressed human autophagin, revealed that the recombinant protein hydrolyzed the synthetic substrate Mca-Thr-Phe-Gly-Met-Dpa-NH2 whose sequence derives from that present around the Apg4 cleavage site in yeast Apg8/Aut7. This proteolytic activity was diminished by N-ethylmaleimide, an inhibitor of cysteine proteases including yeast Apg4/Aut2. These results provide additional evidence that the autophagic process widely studied in yeast can also be fully reconstituted in human tissues and open the possibility to explore the relevance of the autophagin-based proteolytic system in the induction, regulation, and execution of autophagy.

* This work was supported by grants from Comisión Interministerial de Ciencia y Tecnología-Spain (SAF00-0217) and Gobierno del Principado de Asturias-Spain and European Union (QLG1-CT-2000-01131). The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AJ312234, AJ312332, AJ504651, AJ504652, AJ312233, AJ312333, AJ504653, and AJ504654.

§ Recipients of fellowships from Ministerio de Ciencia y Tecnología, Madrid, Spain.

Both authors contributed equally to this work.

** To whom correspondence should be addressed: Dept. de Bioquímica y Biología Molecular Facultad de Medicina, Universidad de Oviedo 33006-Oviedo, Spain. Tel.: 34-985-104201; Fax: 34-985-103564; E-mail: CLO@correo.uniovi.es.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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